Molephantin Derivatives Useful in the Treatment of Cancer

The invention relates to molephantin derivatives, to pharmaceutical formulations comprising the molephantin derivatives, and to medical uses of the molephantin derivatives (e.g. in the treatment of cancers such as colorectal cancer and gastric cancer).

The listing or discussion of a prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or is common general knowledge.

Today, over 60% of anti-cancer drugs are derived in one way or another from plants. Notable plant-derived anti-cancer drugs that are used in clinical practice include the vina alkaloids vinblastine and vincristine, the camptothecin derivatives topotecan and irinotecan and paclitaxel (Taxol) which are isolated or derived from CatharanthusG. Don. (Apocynaceae), CamptothecaDecne (Nyssaceae) andNutt. (Taxaceae), respectively. However, these drugs are often associated with side effects including alopecia, skin reactions, fatigue, and muscle/joint pain.

The number of new cancer cases in low- and middle-income countries is expected to rise by over 80% by 2040. Given this rise and the problems of drug resistance and adverse side effects from current therapies, there is therefore a need for new efficient anti-cancer drugs.

Linn. is a species of perennial flowering plant belonging to the Asteraceae family. It is native to North America but has spread widely to the pantropical regions. In Malaysia, a decoction of the whole plant is used as a diuretic, analgesic, febrifuge, anti-helminthic and anti-inflammatory agent. The leaves of the plant are also applied externally to relieve pain.

Phytochemical studies onL. have isolated compounds including triterpenes, flavonioids, alkaloids, caffeoylquinic acids and sesquiterpene lactones. Tomenphantopin-A and -B are two of the earliest sesquiterpene lactones isolated fromL., and demonstrated cytotoxic activity against human KB oral carcinoma cells with an EDvalue of 2.5 μg/ml and 5.0 μg/ml respectively (Hayashi T, et al., Phytochemistry, vol. 26, 1987, 1065-1068). Since then, many other sesquiterpene lactones have been isolated. Tomenphantine-A and -B were found to inhibit proliferation of KB cell lines with an EDvalue of 3.0 μg/ml and 2.7 μg/ml respectively (Hayashi T, et al., J Nat Prod, vol. 62, 1999, 302-304). Tomenphantopin-D and molephantin had inhibitory activities against human myeloid leukemia cell line K562 and human hepatoma cell line (SMMC-7221) with ICvalues of 44.8 μM and 11.2 μM respectively for Tomenphantopin-D and 7.9 μM and 5.8 μM for molephantin, while Tomenphantopin-C, -E and -F were inactive (Mei W-L et al., Two new Germacranolides from, Phytochemistry Letters, vol. 5, 2012, 800-803 and Wang B, et al., Two New Sesquiterpene Lactones from, Chinese Journal of Chemistry, vol. 30, 2012, 1320-1322).

Although a number of bioactive compounds isolated fromL have shown cancer cell cytotoxicity and antitumor efficacy, these compounds have not yet been evaluated in clinical trials. There is also a lack of in vitro studies on the mechanistic actions of these compounds, as well as in vivo investigations in animal models. Therefore, it is not currently possible to predict whether or not any of the bioactive compounds isolated fromwould actually have efficacy in treating cancer in vivo.

The invention relates to derivatives of molephantin, which itself may be isolated fromL. The derivatives may be prepared by esterification and have surprisingly improved anticancer activity both in vitro and in vivo.

The invention therefore provides the following numbered clauses.

The invention provides a compound of formula I:

Thus, Rmay represent H, —C(O)Ror —C(O)Calkyl, which latter group is unsubstituted or substituted by one or more groups selected from halo and R, or when Rrepresents —C(O)C(═CH)CH, Rmay represent —C(O)Ror —C(O)Calkyl, which latter group is unsubstituted or substituted by one or more groups selected from halo and R.

In other words, when Rrepresents —C(O)C(═CH)CH, then Ris not H.

In some embodiments of the invention that may be mentioned herein, Rmay represent —C(O)Ror —C(O)Calkyl, which latter group is unsubstituted or substituted by one or more groups selected from halo and R.

In some embodiments of the invention that may be mentioned herein, Rmay represent —C(O)C(═CH)CH.

In some embodiments of the invention that may be mentioned herein, Rand Rmay each independently represent H, —C(O)Ror —C(O)Calkyl, which latter group may be unsubstituted or substituted by one or more groups selected from halo and R.

In some such embodiments, Rand Rmay each independently represent —C(O)Ror —C(O)Calkyl, which latter group may be unsubstituted or substituted by one or more groups selected from halo and R.

In some embodiments of the invention that may be mentioned herein, Rmay represent —C(O)Ror —C(O)Calkyl, which latter group may be unsubstituted or substituted by one or more groups selected from halo and R, and Rmay represent —C(O)C(═CH)CH.

In some such embodiments, Rmay represent —C(O)Ror —C(O)Calkyl, which latter group may be unsubstituted or substituted by one or more groups selected from halo and R, and Rmay represent —C(O)C(═CH)CH.

In some embodiments of the invention that may be mentioned herein, Rmay represent —C(O)Rand Rmay represent —C(O)Ror —C(O)C(═CH)CH.

R, when present, represents aryl, cycloalkyl or a heterocyclic ring system, where each of aryl, cycloalkyl and the heterocyclic ring system is unsubstituted or substituted by one or more groups selected from NOand, more particularly, halo and Calkyl, where Calkyl is unsubstituted or substituted by one or more halo groups.

In some embodiments of the invention that may be mentioned herein, R, when present, may represent aryl or a heterocyclic ring system, where each of aryl and the heterocyclic ring system may be unsubstituted or substituted by one or more groups selected from NOand, more particularly, halo and Calkyl, where the Calkyl may be unsubstituted or substituted by one or more halo groups.

In some embodiments of the invention that may be mentioned herein, R, when present, may be aryl that is unsubstituted or substituted by one or more groups selected from NOand, more particularly, halo and Calkyl, where Calkyl is unsubstituted or substituted by one or more halo groups.

In some embodiments of the invention that may be mentioned herein, R, when present, may be phenyl that may be unsubstituted or substituted by one or more groups selected from NOand, more particularly, F and Calkyl, where Calkyl may be unsubstituted or substituted by one or more halo groups.

In any of the above embodiments of the invention, the substituent present on Rmay be substituted by a substituent that is not NO. In other words, in any of the above embodiments of the invention Rmay represent an aryl, cycloalkyl or a heterocyclic ring system (e.g. aryl or a heterocyclic ring system, such as aryl, for example phenyl), where each of aryl, cycloalkyl, the heterocyclic ring system and phenyl may be unsubstituted or substituted by one or more groups selected from halo (e.g. F) and Calkyl (e.g. Calkyl), where the Calkyl (or Calkyl) is unsubstituted or substituted by one or more halo (e.g. F) groups.

R, when present, represents aryl, cycloalkyl or a heterocyclic ring system, where each of aryl, cycloalkyl and the heterocyclic ring system is unsubstituted or substituted by one or more groups selected from halo and Calkyl, where Calkyl is unsubstituted or substituted by one or more halo groups.

In some embodiments of the invention that may be mentioned herein, R, when present, may represent aryl or a heterocyclic ring system, where each of aryl and the heterocyclic ring system may be unsubstituted or substituted by one or more groups selected from halo and Calkyl, where the Calkyl may be unsubstituted or substituted by one or more halo groups. In some embodiments of the invention that may be mentioned herein, R, when present, may be aryl that is unsubstituted or substituted by one or more groups selected from halo and Calkyl, where Calkyl is unsubstituted or substituted by one or more halo groups.

In some embodiments of the invention that may be mentioned herein, R, when present, may be phenyl that may be unsubstituted or substituted by one or more groups selected from F and Calkyl, where Calkyl may be unsubstituted or substituted by one or more halo groups.

In some embodiments of the invention where Ris present, it may be present as a substituent on a methyl group. For example, the Calkyl moiety and Rmay together represent a substituted or unsubstituted benzyl group, where the substituents are as defined above.

Where groups above are referred to as comprising “one or more” substituents, they may be substituted with one substituent or more than one substituent, for example, they may be substituted by one to six substituents, such as one to five substituents, e.g. one; two; or three substituents.

By way of example, when an alkyl group (e.g. a Calkyl group such as methyl) is substituted by one or more substituents (e.g. halo groups), said alkyl group may be substituted by one, two or three substituents (e.g. halo groups). The halo groups may be fluoro groups. An example of an alkyl group substituted with one or more halo (e.g. fluoro) groups is trifluoromethyl.

As a further example, when an aryl group (e.g. a phenyl group) is substituted by one or more substituents, the aryl group may be substituted by one to five substituents (e.g. halo groups or Calkyl groups, which Calkyl groups may themselves be substituted or unsubstituted as defined above). The aryl group may be a phenyl group. The halo groups may be fluoro groups. The Calkyl groups may be as defined above. An example of an aryl group (e.g. phenyl group) substituted with one or more halo (e.g. fluoro) groups is pentafluorophenyl.

Specific compounds according to the invention include the following:

and pharmaceutically acceptable salts and solvates thereof.

In certain embodiments of the invention, the compound of formula I may be selected from:

The invention provides a pharmaceutical formulation including a compound of formula I or a pharmaceutically acceptable salt or solvate thereof, in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier.

The compounds of formula I have anticancer activity. As such, the invention provides the following.

In each of the above use, compound for use and method of treatment, the cancer may be selected from one or more of the group selected from adrenal cancer, anal cancer, bile duct cancer, bladder cancer, bone cancer, brain tumours, CNS tumours, breast cancer, Castleman disease, cervical cancer, colon cancer, rectum cancer, colorectal cancer, endometrial cancer, esophagus cancer, eye cancer, gallbladder cancer, gastrointestinal carcinoid tumors, gastric cancer, gastrointestinal stromal tumor (GIST), gestational trophoblastic disease, Hodgkin disease, Kaposi sarcoma, kidney cancer, laryngeal cancer, hypopharyngeal cancer, leukemia (e.g. acute lymphocytic, acute myeloid, chronic lymphocytic, chronic myeloid, chronic myelomonocytic), liver cancer, lung cancer (e.g. small cell or non-small cell), lung carcinoid tumour, lymphoma (e.g. of the skin), malignant mesothelioma, multiple myeloma, myelodysplastic syndrome, nasal cavity cancer, paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, oral cavity cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, penile cancer, pituitary tumours, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, skin cancer (basal and squamous cell, melanoma, Merkel cell), small intestine cancer, stomach cancer, testicular cancer, thymus cancer, thyroid cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenstrom macroglobulinemia, Wilms tumour.

In some embodiments of the invention that may be mentioned herein, the cancer may be selected from colorectal cancer and gastric cancer.

The word “comprising” refers herein may be interpreted as requiring the features mentioned, but not limiting the presence of other features. Alternatively, the word “comprising” may also relate to the situation where only the components/features listed are intended to be present (e.g. the word “comprising” may be replaced by the phrases “consists of” or “consists essentially of”). It is explicitly contemplated that both the broader and narrower interpretations can be applied to all aspects and embodiments of the present invention. In other words, the word “comprising” and synonyms thereof may be replaced by the phrase “consisting of” or the phrase “consists essentially of” or synonyms thereof and vice versa.

The phrase, “consists essentially of” and its pseudonyms may be interpreted herein to refer to a material where minor impurities may be present. For example, the material may be greater than or equal to 90% pure, such as greater than 95% pure, such as greater than 97% pure, such as greater than 99% pure, such as greater than 99.9% pure, such as greater than 99.99% pure, such as greater than 99.999% pure, such as 100% pure.

As used herein, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise.

References herein (in any aspect or embodiment of the invention) to compounds of formula I includes references to such compounds per se, to tautomers of such compounds, as well as to pharmaceutically acceptable salts or solvates, or pharmaceutically functional derivatives of such compounds.

Pharmaceutically acceptable salts that may be mentioned include acid addition salts and base addition salts. Such salts may be formed by conventional means, for example by reaction of a free acid or a free base form of a compound of formula I with one or more equivalents of an appropriate acid or base, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, using standard techniques (e.g. in vacuo, by freeze-drying or by filtration). Salts may also be prepared by exchanging a counter-ion of a compound of formula I in the form of a salt with another counter-ion, for example using a suitable ion exchange resin.

Examples of pharmaceutically acceptable salts include acid addition salts derived from mineral acids and organic acids, and salts derived from metals such as sodium, magnesium, or preferably, potassium and calcium.

Examples of acid addition salts include acid addition salts formed with acetic, 2,2-dichloroacetic, adipic, alginic, aryl sulphonic acids (e.g. benzenesulphonic, naphthalene-2-sulphonic, naphthalene-1,5-disulphonic and p-toluenesulphonic), ascorbic (e.g. L-ascorbic), L-aspartic, benzoic, 4-acetamidobenzoic, butanoic, (+) camphoric, camphor-sulphonic, (+)-(1S)-camphor-10-sulphonic, capric, caproic, caprylic, cinnamic, citric, cyclamic, dodecylsulphuric, ethane-1,2-disulphonic, ethanesulphonic, 2-hydroxyethanesulphonic, formic, fumaric, galactaric, gentisic, glucoheptonic, gluconic (e.g. D-gluconic), glucuronic (e.g. D-glucuronic), glutamic (e.g. L-glutamic), α-oxoglutaric, glycolic, hippuric, hydrobromic, hydrochloric, hydriodic, isethionic, lactic (e.g. (+)-L-lactic and (±)-DL-lactic), lactobionic, maleic, malic (e.g. (−)-L-malic), malonic, (±)-DL-mandelic, metaphosphoric, methanesulphonic, 1-hydroxy-2-naphthoic, nicotinic, nitric, oleic, orotic, oxalic, palmitic, pamoic, phosphoric, propionic, L-pyroglutamic, salicylic, 4-amino-salicylic, sebacic, stearic, succinic, sulphuric, tannic, tartaric (e.g. (+)-L-tartaric), thiocyanic, undecylenic and valeric acids.